This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of the research in my laboratory is to dissect the cellular activities of NR4A NRs in the genetic model organism C. elegans. The cellular activities of NR4A, including mechanisms of transcriptional regulation and interactions with signal transduction pathways, are poorly understood. We have identified an organogenesis function for the C. elegans NR4A ortholog, NHR-6, in C. elegans. The INBRE funded project in my laboratory has two primary objectives: test the hypothesis that NHR-6 functions as an organ specific regulator of cell cycle progression and cell differentiation;and 2) to identify the cellular mechanisms of NHR-6 activity. Data from this work will provide key insight into the functions of this group of physiologically and developmentally important proteins with emerging human health relevance. This past year we pursued two specific aims. The first was to further characterize the genetic interactions between NHR-6 and Eph receptor signaling and to test the hypothesis that NHR-6 and Eph receptor signaling function in a common pathway. The second aim was to determine if NHR-6 functions through a DNA-binding mechanism. Significant progress has been made on the first aim. We have generated data that suggest NHR-6 and Eph receptor function in a late step in spermatheca development. We also have genetic evidence indicating that NHR-6 and Eph receptor signaling function in a common pathway. For the second aim, we have demonstrated using genetic rescue assays that the NHR-6 DNA-binding domain is necessary for its in vivo function and we are currently pursuing experiments to identify downstream target genes.